Osmotic delivery systems, manufactured as an osmotic delivery device, for delivering useful agents are becoming increasingly important articles of commerce and manufacture. These osmotic devices enjoy a wide application in the pharmaceutical, veterinary, husbandry and agriculture industries. The osmotic devices used by these industries exhibit a beneficial agent release rate that is substantially constant, once thermodynamic steady state conditions are established by the osmotic device. If the thermodynamic activity of the beneficial agent is maintained substantially constant in the device, then a steady state will be established with the release rate of agent from the device being constant over a prolonged period of time. This is commonly referred to as zero order release, a phrase suggested by physical-chemical kinetics.
The above described osmotic systems represent an outstanding advancement in the zero order delivery art for dispensing a beneficial agent continuously and at a constantly controlled rate. Now, it has been unexpectedly discovered a therapeutic result can be effected by a pulse dose of agent delivery. For example, estradiol administered at a low pulsed dose inhibits gonada-tropin secretion, while at high pulsed doses estradiol stimulates the ovulating surge of gonadotropin secretion, as reported in Drugs, Vol. 23, pages 207-226, 1982. Other therapeutic agents that produce a beneficial medical effect in this manner are pulsed methylprednisolone treatment of collagenic and progressing glomerulonephritis; pulsed cyclophosphamide-vincristine-adriamycin to patients suffering with neuroblastoma; pulsed rifampicin therapy in leprosy; pulsed oxytocin in the induction of labor; and pulsed insulin for the control of hyperglycemia; as reported in Fertil. and Steril., Vol. 39, pages 695-699, 1983; Vutr. Boles, Vol. 21, pages 65-74, 1982; Br. J. Cancer, Vol. 45, pages 86-94, 1982; Fert. and Steril., Vol. 36, pages 553-559, 1981; Int. J. Radiat. Oncol. Biol. Phys., Vol. 8, pages 915-919, 1982; J. Clin. Endocrinol. Metab., Vol. 53, pages 184-91, 1981; and, Diabetes, Vol. 26, pages 571-581, 1977.
Heretobefore, the prior art lacked a delivery system for administering a useful agent at a pulsed rate, particularly at a pulsed rate joined with a zero order rate of delivery. Thus, in the light of the above presentation, it will be readily appreciated by those versed in the dispensing art, that a critical need exists for a delivery system that can deliver a useful agent at a substantial zero order rate which is (a) preceeded by a pulsed delivery of the useful agent, (b) interrupted by a pulsed delivery of the agent, (c) terminated by a pulsed delivery of the agent, or (d) is a terminal pulse followed by a substantially constant delivery from the osmotic system. It will be further appreciated by those versed in the art, that it is a novel and useful device made available for delivering an agent at a constant rate and pulsed rate, such a device would have a positive value and also represent a valuable contribution to the dispensing art.